Synthesis and biological evaluation of new rhodanine analogues bearing 2-chloroquinoline and benzo[h]quinoline scaffolds as anticancer agents

Article abstract of DOI:10.1016/j.ejmech.2014.06.013

Several rhodanine derivatives (9-39) were synthesized for evaluation of their potential as anticancer agents. Villsmeier cyclization to synthesize aza-aromatic aldehydes, rhodanine derivatives preparation and Knoevenagel type of condensation between the rhodanines and aza-aromatic aldehydes are key steps used for the synthesis of 31 compounds. In vitro antiproliferative activity of the synthesized rhodanine derivatives (9-39) was studied on a panel of six human tumor cell lines viz. HGC, MNK-74, MCF-7, MDAMB-231, DU-145 and PC-3 cell lines. Some of the compounds were capable of inhibiting the proliferation of cancer cell lines at a micromolar concentration. Six compounds are found to be potent against HGC cell lines; compound 15 is found to be active against HGC - Gastric, MCF7 - Breast Cancer and DU145 - Prostate Cancer cell lines; compound 39 is potent against MNK-74; four compounds are found to be potent against MCF-7 cell lines; three compounds are active against MDAMB-231; nine compounds are found to be potent against DU-145; three compounds are active against PC-3 cell lines. These compounds constitute a promising starting point for the development of novel and more potent anticancer agents in future.

Full text of DOI:10.1016/j.ejmech.2014.06.013

Accepted Manuscript
Synthesis and biological evaluation of new rhodanine analogues bearing 2-
chloroquinoline and benzo[h]quinoline scaffolds as anticancer agents
Vadla Ramesh, Boddu Ananda Rao, Pankaj Sharma, B. Swarna, Dinesh Thummuri,
Kolupula Srinivas, V.G.M. Naidu, Vaidya Jayathirtha Rao
PII:
S0223-5234(14)00532-7
10.1016/j.ejmech.2014.06.013
EJMECH 7056
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 21 April 2014
Revised Date: 31 May 2014
Accepted Date: 8 June 2014
Please cite this article as: V. Ramesh, B.A. Rao, P. Sharma, B. Swarna, D. Thummuri, K. Srinivas,
V.G.M. Naidu, V.J. Rao, Synthesis and biological evaluation of new rhodanine analogues bearing 2-
chloroquinoline and benzo[h]quinoline scaffolds as anticancer agents, European Journal of Medicinal
Chemistry (2014), doi: 10.1016/j.ejmech.2014.06.013.
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ACCEPTED MANUSCRIPT
Synthesis and biological evaluation of new rhodanine analogues bearing 2-
chloroquinoline and benzo[h]quinoline scaffolds as anticancer agents
Vadla Ramesh, Boddu Ananda Rao, Pankaj Sharma, B. Swarna, Dinesh Thummuri,
Kolupula Srinivas, V.G.M. Naidu, Vaidya Jayathirtha Rao

ACCEPTED MANUSCRIPT
Synthesis and biological evaluation of new rhodanine analogues bearing
2
-chloroquinoline and benzo[h]quinoline scaffolds as anticancer agents
a,b
a,b
a,c
d
d
Vadla Ramesh, Boddu Ananda Rao , Pankaj Sharma , B. Swarna , Dinesh Thummuri ,
c
d
a,b,c
Kolupula Srinivas* , V.G.M. Naidu* , Vaidya Jayathirtha Rao *
a
b
Crop Protection Chemicals Division, AcSIR-IICT, CSIR-Indian Institute of Chemical
Technology, Uppal Road Tarnaka, Hyderabad 500007, India
c
d
Department of Medicinal Chemistry, Department of Pharmacology & Toxicology,
National Institute of Pharmaceutical Education & Research, Balanagar, Hyderabad 500037, India
Corresponding Author Email: jrao@iict.res.in; vgmnaidu@niperhyd.ac.in; ksrinivas07@yahoo.com
Abstract
Several rhodanine derivatives (9-39) were synthesized for evaluation of their potential as
anticancer agents. Villsmeier cyclization to synthesize aza-aromatic aldehydes, rhodanine
derivatives preparation and Knoevenagel type of condensation between the rhodanines and aza-
aromatic aldehydes are key steps used for the synthesis of 31 compounds. In vitro
antiproliferative activity of the synthesized rhodanine derivatives (9-39) was studied on a panel
of six human tumor cell lines viz. HGC, MNK-74, MCF-7, MDAMB-231, DU-145 and PC-3
cell lines. Some of the compounds were capable of inhibiting the proliferation of cancer cell lines
at a micromolar concentration. Six compounds are found to be potent against HGC cell lines;
compound 15 is found to be active against HGC - Gastric, MCF7 - Breast Cancer and DU145 -
Prostate Cancer cell lines; compound 39 is potent against MNK-74; four compounds are found to
be potent against MCF-7 cell lines; three compounds are active against MDAMB-231; nine
compounds are found to be potent against DU-145; three compounds are active against PC-3 cell
lines. These compounds constitute a promising starting point for the development of novel and
more potent anticancer agents in future.
Keywords: Anilides Villsmeier Reaction; 2-Chloroquinoline-3-carbaldehydes; Rhodanine
Derivatives; Anticancer Activity.
1

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1
. Introduction
Rhodanine is a five-membered heterocyclic ring with diverse applications particularly in
biochemistry, medicinal chemistry, photochemistry, industry and coordination chemistry [1]. In a
recent review, rhodanine was reported as privileged scaffold in drug discovery whose
functionalization and appropriate modifications led to compounds endowed with various
biological activities [1a,1c]. Substituted rhodanine compounds have been investigated for a wide
range of pharmacologic indications such as fungal protein mannosyl transferase-1 inhibitors [2],
PDE4 inhibitors [3], protease inhibitors [4], JNK stimulating phosphatase-1 (JSP-1) inhibitors
[5], UDP-N-acetylmuramate/L-alanine ligase [6], antimalerials [7], HIV-1 Integrase inhibitors
[8], aldose reductase inhibitors[9], β-lactamase inhibitors[10], antidiabetic agents [11], HCV
NS3 protease inhibitor [12], histidine decarboxylase inhibitors [13], ADAMTS-5 inhibitors [14],
MurD ligase inhibitors [15] T. brucei dolicholphosphate mannose synthase (DPMS) inhibitors
[16], antibacterials [17], Photosynthesis inhibitor [18], Anthrax lethal factor protease inhibitor
[19] etc. Epalrestat is a rhodanine analogue and marketed drug as aldose reductase inhibitor in
Japan, China and India [20]. Recently we have reported aldose reductase inhibitory activity of
rhodanine derivatives whose potency is equivalent to marketed drug epalrestat [9a]. The
attention of scientists around the globe has focused on anticancer effects of rhodanine
compounds [21a-q]. In this context, we have reported the synthesis and anticancer activity of
some rhodanine derivatives appended with 2-chloropyridine scaffold [21m]. Rhodanine with
quionoline derivatives also exhibit various pharmacological activities [22]. In continuation to our
work, we present here the synthesis and anticancer activity of newer rhodanine derivatives.
These
compounds
possess
2-chloroquinoline,
2-piperidinequinoline
and
2-
chlorobenzo[h]quinoline pharmacophore as appendages to rhodanine scaffold. In this work, 31
new compounds were synthesized and screened against six human cancer cell lines. Good
number of compounds were found to exhibit potency compared to our previous series of
compounds carrying 2-chloropyridine with rhodanine fragment [21m].
2
. Results and discussion
2
.1. Chemistry
2

ACCEPTED MANUSCRIPT
The synthesis of 31 new quinoline-rhodanine derivatives 9 - 39 were accomplished as outlined in
Schemes 1 to 7. The synthetic strategy involves in making quinoline and rhodanine residues
(Scheme 1 to 3) and taking them for condensation (Schemes 4 to 7) leading to desired target
molecules 9 - 39. Various anilines (1a-l) were treated with acetylchloride (Scheme 1) to get
corresponding anilides (2a-l) and subsequent Villsmeier reaction using 3a-l anilides provided
chloroquinolinealdehydes 3a-l (Scheme 1) in good yields [23]. Some selected 2-chloroquinoline-
3
-carbaldehydes 3a, 3b, 3c and 3e were reacted with piperidine 4a to make piperidine coupled
quinolinecarabaldehydes 5a-d (Scheme 2). 2-Chloroquinoline-3-carbaldehyde 3e was reacted
with morpholine 4b to get morpholine coupled quinolinecarbaldehyde 5e, under nucleophilic
substitution conditions. Rhodanine compounds 8a-c were prepared as outlined in Scheme 3.
Ammonium dithiacarbamates 7a-c were obtained by treating respective amine derivatives 6a-c
with carbondisulfide and ammonia [21q, 24]. In second step, 7a-c were reacted with
sodiumchloroacetate at higher temperature to afford rhodanine derivatives 8a-c in good yield
(
Scheme 3). Synthesized aldehydes 3a-l were reacted with rhodanine 8a in the presence of
sodiumacetate and acetic acid to get target compounds 9-20 (Scheme 4) [21q]. Compounds 21-
1 were synthesized by similar approach of above i.e. coupling 3a-b and 3d-m with rhodanine
3
acetic acid (Scheme 5). Rhodanine derivatives 32-34 were synthesized by condensation between
the requisite phenyl rhodanine 8c and 2-chloroquinoline-3-carboxaldehydes, 3f and 3g in the
presence of sodium acetate and acetic acid under reflux conditions (Scheme 6). In a similar
manner, 2-piperizinequinoline-3-carbaldehydes 5a-e were treated with rhodanine 8a and
rhodanine acetic acid 8b separately to afford compounds 35-39 (Scheme 7). All the synthesized
compounds (Table 1) gave satisfactory analytical and spectroscopic data (NMR, Mass and IR
etc,), which were in full accordance with their depicted structures.
Schemes 1 to 7 and Table 1
2
.2. Biological activity
All the synthesized compounds were screened against six cancer cell lines viz., HGC, MNK-74,
MCF-7, MDAMB-231, DU-145 and PC-3 cell lines to test their potential to serve as anticancer
agents. The anticancer activities of synthesized compounds (9-39) were evaluated by MTT [3-(4,
5
-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] method using gastric (HGC, MNK-
3

ACCEPTED MANUSCRIPT
7
4), breast (MCF-7, MDAMB-231) and prostate (DU-145 and PC-3) cancer cell lines. The
compounds were screened with various cancer cell lines at 100 µM concentration, dose response
Table 2 and Figure 1
was done for the compounds exhibiting greater than 50% inhibition and IC50 of those compounds
only are reported (Table 2). The effect of selected compounds on the cell viability for each cell
line after exposure to different concentrations is depicted in Fig. 1. Compounds 14, 15, 16, 18, 35
and 39 are potent against HGC cell lines. Most of these compounds possess free amine group on
rhodanine moiety except compound 11. Remaining compounds are less active. In case of MNK-
7
4, compound 39 is most active with IC50 of 13.9±2.3 µm among the tested compounds.
Compounds 14 and 35 are moderately active. Synthesized compounds were screened against
MCF-7 cell lines, compounds 9, 12, 15 and 20 are active with the inhibition range of 6.3±0.8 to
1
1.8±2.2 µm. Compound 13 is moderately active and rest of the compounds are inactive.
Compounds 15, 20 and 36 are moderately active against MDAMB-231 cell lines and rest of the
molecules is inactive. In case of DU-145, compounds 14, 15, 16, 18, 19, 20, 25, 35 and 39 are
active molecules. Most of these compounds are rhodanine with free amine group. Compounds
1
0, 11, 12, 13, 19, 26, 36 are moderately active. Compounds 15, 35 and 39 are active among the
screened compounds against PC-3 cell lines and rest of the compounds is inactive. Among the
six cell lines, structure-activity relationships (SAR) of two cell lines only (HGC and DU145) in
view of dispersion of compounds on observed range of activity. SAR data inferred that
rhodanine compounds possessing free –NH- are more active over their counter parts such as –N-
CH -COOH and –N-Ph derivatives. Substitution on quinoline ring with methyl or ethyl group
2
(10-13) favored anticancer activity over unsubstituted derivative 9. Additional methyl
substitution either on C-5 (compound 15) or C-6 (compound 14) of compound 10 resulted more
potency with IC of 7.2±0.5 or 9.7±1.5 µM respectively. It seems that hydrophobic groups on
5
0
quinoline favors improved anticancer activity. C-6 methoxy substituted derivative 16 is more
potent over compound 9 (unsubstituted derivative) and compound 13 (methyl substituted
derivative). In case of dimethoxy substitution either at C-6 and C-7 position (compound 18) or at
C-5 and C-8 position (compound 17), reduced activity is observed. Replacement of chlorine
group with piperazine or morpholine indicated improved anticancer activity compared to
4

ACCEPTED MANUSCRIPT
compound 9. In case of DU145 cancer cell lines, substitution like methyl, ethyl, dimethyl,
methoxy, dimethoxy etc on quinoline ring enhances the anticancer activity compared to
compound 9. Substitution of piperazine or morpholine in place of ‘Cl’ (compounds 35 and 36)
improved the activity. Replacement of rhodanine with rhodanine acetic acid (compound 26) does
not change much in the activity but in other cases decreased activity was noticed. Our future
work will be focused on synthesis of newer analogues rationally designed based on the SAR data
and target oriented molecular mechanistic studies.
3
. Conclusion
In this article, several new rhodanine derivatives that may function as anticancer agents have
been synthesized using 2-chloroquinoline-3-carbaldehydes. In vitro anticancer activity of these
compounds was evaluated over six human cancer cell lines. Some of the synthesized compounds
displayed potent anti cancer activity. Six compounds are found to be potent against HGC cell
lines; compound 39 is potent against MNK-74; four compounds are found to be potent against
MCF-7 cell lines; three compounds are active against MDAMB-231; nine compounds are found
to be potent against DU-145; three compounds are active against PC-3 cell lines. Some of these
compounds would serve as potential anticancer agents with modifications on pharmacophore.
4
.0. Experimental section
4
.1 Chemistry
General: All commercially available chemicals were used without further purification. Melting
points were determined on a Mel-Temp apparatus and are uncorrected. IR spectra were recorded
using a Thermo Nicolet Nexus 670 FTIR spectrometer. The NMR spectra were recorded on
1
13
Brucker Avance 300 magnetic resonance spectrometer at 300 MHz for H and 500 MHz for C
respectively, using TMS as internal standard. The chemical shifts are expressed as δ values in
parts per million (ppm) and the coupling constants (J) are given in hertz (Hz). ESI-MS were
obtained on Thermo-Finnigan MAT-1020B instrument. Elemental analyses were carried out with
a Perkin Elmer 2400 Series II elemental analyzer. Column chromatography was performed on
silica gel (60-120 mesh, Acme, India).
2
-Chloroquinoline-3-carbaldehyde derivatives (3a-l) were prepared as per the literature [24].
5

ACCEPTED MANUSCRIPT
4
.2. General procedure for the synthesis of substituted 2-(piperidin-1-yl)quinoline-3-
carbaldehyde
-Chloro-3-formyl quinoline 3a, 3b, 3c and 3e (0.001 mol) and potassium carbonate (0.002 mol)
2
was taken in round bottom flask and 4a or 4b in excess was added. The mixture was refluxed for
0
4
hours at 200 C. Reaction was monitored by TLC. After completion of the reaction, the
reaction mass was cooled to room temperature and poured on to water. It was then filtered
through the suction pump, washed with water and dried. The crude product thus obtained was
then purified by column chromatography (ethyl acetate-hexane).
4
.2.1. 2-(Piperidin-1-yl)quinoline-3-carbaldehyde (5a):
0
1
Yellow solid; Yield: 75%; mp: 81-83 C. H NMR (500 MHz, CDCl ): δ 10.10 (s, 1H), 8.46 (s,
3
H), 7.80 (d, 1H, J = 8.12 Hz), 7.74 (d, 1H, J =8.68 Hz), 7.65 (t, 1H, J = 6.98 Hz ), 7.34 (t, 3H, J
+
=
6.98 Hz), 3.43 (m, 4H), 1.75 (m, 6H); MS(ESI) m/z (%): 241 [M+H] .
4
.2.2. 8-Methyl-2-(piperidin-1-yl)quinoline-3-carbaldehyde (5b):
0
1
Yellow solid; Yield: 78%; mp: 83-85 C. H NMR (500 MHz, CDCl ) δ: 10.16 (s, 1H), 8.44 (s,
3
H), 7.81 (d, 1H, J = 8.30 Hz), 7.63 (d, 1H, J =8.30 Hz), 7.24 (t, 1H, J = 8.30 Hz ) 3.48 (m, 4H),
+
1
.75 (m, 6H), 1.57 (s, 3H); MS(ESI) m/z (%): 255 [M+H] .
4
.2.3. 8-Ethyl-2-(piperidin-1-yl)quinoline-3-carbaldehyde (5c):
0
1
Yellow solid; Yield: 80%; mp: 82-84 C. H NMR (500 MHz, CDCl ): δ 10.00 (s, 1H), 8.50 (s,
3
H), 7.80 (d, 1H, J = 8.12 Hz), 7.74 (d, 1H, J =8.68 Hz), 7.65 (t, 1H, J = 8.68 Hz ), 2.54 (q, 2H, J
+
=
6.98 Hz), 3.43 (m, 4H), 1.75 (m, 6H), 1.50 (t, 3H, J =6.98 Hz); MS(ESI) m/z (%): 269 [M+H] .
4
.2.4. 6-Methyl-2-(piperidin-1-yl)quinoline-3-carbaldehyde (5d):
0
1
Yellow solid; Yield: 78%; mp: 91-93 C. H NMR (500 MHz, CDCl ): δ 10.16 (s, 1H), 8.41 (s,
3
H), 7.73 (d, 1H, J = 8.30 Hz), 7.54 (s, 1H), 7.51 (d, 1H, J =8.30 Hz), 3.41 (m, 4H), 1.75 (m, 6H),
+
1
.59 (s, 3H); MS(ESI) m/z (%): 255 [M+H] .
6

ACCEPTED MANUSCRIPT
4
.2.5. 6-Methyl-2-morpholinoquinoline-3-carbaldehyde (5e):
0
1
Yellow solid; Yield: 79%; mp: 93-95 C. H NMR (500 MHz, CDCl ) δ: 10.15 (s, 1H), 8.42 (s,
3
H), 7.69 (d, 1H, J = 8.49 Hz), 7.59 (s, 1H), 7.52 (d, 1H, J =8.49 Hz), 3.86 (t, 3H, J =4.34 Hz )
+
3
.46 (t, 3H, J =4.34 Hz), 2.50 (s, 3H); MS(ESI) m/z (%): 257 [M+H] .
Rhodanine (8a), rhodanine aceticacid (8b) and N-phenylrhodanine (8c) were prepared as per the
literature [21q, 23].
4
2
2
.3. General procedure for the synthesis of rhodanine derivatives (9-20).
-Chloroquinoline-3-carbaldehyde 3a-n (0.0045 mol) was taken in round bottom flask added to
-thioxothiazolidin-4-one 8a (0.0045 mol) and to this sodium acetate (0.0135 mol) was added.
0
Acetic acid (20 ml) was added as solvents. The mixture was refluxed for 4 h at 110 C and
cooled to room temperature and poured into water. It was then filtered through the suction pump,
washed with water to remove excess of acetic acid and recrystallized from methanol to afford
compounds 9-20 [25].
4
.3.1. (Z)-5-((2-Chloroquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (9)
0
1
Yellow solid; Yield: 66%; mp: 345-347 C. H NMR (500 MHz, DMSO-d
6
): δ 8.27 (s, 1H), 7.83
(d, 1H, J = 7.55 Hz), 7.63 (s, 1H), 7.61 (t, 1H, J = 7.55 Hz), 7.34 (d, 1H, J = 7.55 Hz), 7.25 (t,
1
3
1
1
1
2
6
H, J = 7.55 Hz); C NMR (500 MHz, DMSO-d ): δ 197.8, 160.5, 143.8, 139.1, 132.4, 129.2,
-1
27.4, 127.1, 124.5, 122.7, 119.2, 118.5, 115.2. IR (KBr, cm ): 3434, 3092, 2850, 1712, 1546,
+
448, 1212, 748; MS (ESI) m/z (%): 307[M-H] . Anal. calcd for C H ClN OS : C, 50.89; H,
1
3
7
2
2
.30; N, 9.13; S, 20.90. Found: C, 51.24; H, 2.63; N, 9.45; S, 20.38.
4
.3.2. (Z)-5-((2-Chloro-8-methylquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (10)
0
1
Red solid; Yield: 69%; mp: 334-336 C. H NMR (500 MHz, DMSO-d ): δ 8.21 (s, 1H), 7.70 (d,
6
1
H, J = 8.12 Hz), 7.59 (s, 1H), 7.11 (t, 1H, J = 5.28 Hz), 7.08 (d, 1H, J = 8.12 Hz), 2.44 (s, 3H);
1
3
6
C NMR (500 MHz, DMSO-d ): δ 197.8, 169.5, 160.9, 144.4, 137.5, 133.5, 127.3(2), 127.1,
-1
1
24.1, 123.6, 122.4, 119.2, 17.0; IR (KBr, cm ): 3150, 3028, 2362, 1719, 1661, 1232, 740. MS
7

ACCEPTED MANUSCRIPT
+
(
ESI) m/z (%): 319[M+H] . Anal. calcd for C14
9 2 2
H ClN OS : C, 52.41; H, 2.83; N, 8.73; S, 19.99.
Found: C, 52.76; H, 3.02; N, 8.34; S, 19.61.
4
.3.3. (Z)-5-((2-Chloro-8-ethylquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (11)
0
1
Red solid; Yield: 72%; mp: 340-343 C. H NMR (300 MHz, DMSO-d ): δ 8.09 (s, 1H), 7.64 (s,
6
1
H), 7.56 (d, 1H, J = 7.55 Hz), 7.38 (d, 1H, J = 7.55 Hz), 7.14 (t, 1H, J = 7.55 Hz), 2.89 (q, 2H,
13
J = 7.36 Hz), 1.22 (t, 3H, J = 7.55 Hz). C NMR (500 MHz, DMSO-d ) δ: 189.2, 164.5, 162.4,
6
-
1
1
3
56.4, 151.8, 149.9, 149.3, 147.2, 147.2, 143.6, 142.5, 142.3, 139.1, 42.3, 33.8. IR (KBr, cm ):
+
166, 3025, 2362, 1690, 1646, 1440, 1227, 669. MS(ESI) m/z (%): 333[M-H] . Anal. calcd for
C H ClN OS : C, 53.80; H, 3.31; N, 8.37; S, 19.15. Found: C, 54.16; H, 3.54; N, 8.68; S,
15
11
2
2
1
9.28.
4
.3.4. (Z)-5-((2-Chloro-7-methylquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (12)
0
1
Red solid; Yield: 69%; mp: 358-362 C. H NMR (500 MHz, DMSO-d
H), 7.54 (d, 1H, J = 7.93 Hz), 7.11 (s, 1H), 6.99 (d, 1H, J = 7.93 Hz), 2,44 (s, 3H); C NMR
500 MHz, DMSO-d ): δ 197.8, 169.5, 160.6, 143.7, 143.2, 139.3, 129.0, 127.6, 126.4, 124.2,
6
): δ 7.97 (s, 1H), 7.64 (s,
1
3
1
(
6
-1
1
23.4, 117.2, 114.8, 21.6. IR (KBr, cm ): 3143, 2851, 2363, 1699, 1658, 1437, 1220, 678;
+
MS(ESI) m/z (%): 319[M+H] . Anal. calcd for C H ClN OS : C, 52.41; H, 2.83; N, 8.73; S,
14
9
2
2
1
9.99. Found: C, 52.68; H, 3.13; N, 8.45; S, 19.64.
4
.3.5. (Z)-5-((2-Chloro-6-methylquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (13)
0
1
Yellow solid; Yield: 69%; mp: 345-347 C. H NMR (500 MHz, DMSO-d ): δ 8.15 (s, 1H), 8.11
6
13
(
s, 1H), 7.64 (s, 1H), 7.57 (d, 1H, J = 7.17 Hz), 7.37 (d, 1H, J = 7.17 Hz), 2.45 (s, 3H); C NMR
(
500 MHz, DMSO-d ): δ 198.5, 160.9, 144.3, 142.2, 134.4, 133.9, 132.3, 132.0, 129.0, 128.2,
6
-
1
1
3
5
24.6, 119.7, 115.7, 20.8. IR (KBr, cm ): 3075, 1643, 1448, 1217, 929. MS(ESI) m/z (%):
+
19[M+H] . Anal. calcd for C14
H
9
ClN
2
OS
2
: C, 52.41; H, 2.83; N, 8.73; S, 19.99. Found: C,
2.69; H, 3.10; N, 8.36; S, 20.07.
4
.3.6. (Z)-5-((2-Chloro-6,8-dimethylquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (14)
0
1
Red solid; Yield: 72%; mp: 315-317 C. H NMR (300 MHz, DMSO-d ): δ 8.31 (s, 1H), 8.15 (s,
6
1
3
1
H), 7.75 (s, 1H), 7.57 (s, 1H), 2.61 (s, 3H), 2.46 (s, 3H). C NMR (500 MHz, DMSO-d
6
): δ
8

ACCEPTED MANUSCRIPT
1
2
6
8
97.9, 169.4, 160.7, 144.2, 137.8, 137.5, 135.1, 134.6, 131.4, 127.5, 126.6, 125.5, 124.6, 21.0,
-1
0.1. IR (neat, cm ): 3003, 2860, 2358, 2341, 1695, 1651, 1558, 1232, 1215, 1136, 1018, 844,
+
80; MS(LCMS) m/z (%): 335[M+H] . Anal. calcd for C H ClN OS : C, 53.80; H, 3.31; N,
1
5
11
2
2
.37; S, 19.15. Found: C, 53.56; H, 3.59; N, 8.09; S, 18.78.
4
.3.7. (Z)-5-((2-Chloro-5,8-dimethylquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (15)
0
1
Yellow solid; Yield: 72%; mp: 369-371 C. H NMR (300 MHz, DMSO-d ): δ 8.42 (s, 1H), 7.81
6
13
(
s, 1H), 7.48 (d, 1H, J = 6.98 Hz), 7.30 (d, 1H, J = 6.98 Hz), 2.69 (s, 3H), 2.62 (s, 3H); C NMR
500 MHz, DMSO-d ): δ 198.2, 169.5, 160.6, 148.1, 145.8, 142.1, 135.3, 133.5, 133.5, 132.3,
(
6
-
1
1
1
28.3, 124.7, 123.6, 17.9, 17.1; IR (neat, cm ): 3140, 3095, 2854, 2358, 1695, 1685, 1570, 1436,
+
357, 1305, 1215, 1186, 798, 675; MS(LCMS) m/z (%): 333[M-H] . Anal. calcd for
C H ClN OS : C, 53.80; H, 3.31; N, 8.37; S, 19.15. Found: C, 54.15; H, 3.43; N, 7.99; S,
15
11
2
2
1
9.23.
4
.3.8. (Z)-5-((2-Chloro-6-methoxyquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (16)
0
1
Red solid; Yield: 75%; mp: 347-349 C. H NMR (500 MHz, DMSO-d
H), 7.27 (d, 1H, J = 9.06 Hz), 7.20 (s 1H), 7.12 (d, 1H, J = 9.06 Hz), 3.83 (s, 3H); C NMR
500 MHz, DMSO-d ): δ 198.0, 169.9, 160.6, 155.3, 143.3, 141.8, 134.6, 127.8, 125.6, 122.7,
6
): δ 8.00 (s, 1H), 7.66 (s,
1
3
1
(
6
-1
1
20.3, 117.4, 110.8, 56.2; IR (KBr, cm ): 3150, 3074, 2842, 2362, 1696, 1576, 1199, 810;
+
MS(ESI) m/z (%): 335[M-H] . Anal. calcd for C H ClN O S : C, 49.92; H, 2.69; N, 8.32; S,
14
9
2
2 2
1
9.04. Found: C, 50.20; H, 2.42; N, 7.99; S, 18.95.
4
.3.8. (Z)-5-((2-Chloro-5,8-dimethoxyquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (17)
0
1
Red solid; Yield: 76%; mp: 309-312 C. H NMR (300 MHz, DMSO-d
6
): δ 8.28 (s, 1H), 7.65 (s,
-
1
H), 7.18 (d, 1H, J = 8.87 Hz), 7.71 (d, 1H, J = 8.87 Hz), 3.91 (s, 3H), 3.85 (s, 3H); IR (neat, cm
1
): 3161, 3010, 2835, 2358, 2341, 1716, 1647, 1217, 1022, 1002, 823, 667; MS(ESI) m/z (%):
+
3
4
65[M-H] . Anal. calcd for C H ClN O S : C, 49.11; H, 3.02; N, 7.64; S, 17.48. Found: C,
1
5
11
2
3 2
9.39; H, 2.82; N, 7.34; S, 17.10.
4
.3.9. (Z)-5-((2-chloro-6,7-dimethoxyquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (18)
9

ACCEPTED MANUSCRIPT
0
1
6
Red solid; Yield: 76%; mp: 306-310 C. H NMR (300 MHz, DMSO-d ): δ 8.30 (s, 1H), 7.78 (s,
1
3
1
1
5
H), 7.73 (s, 1H), 7.38 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H). C NMR (500 MHz, DMSO-d ): δ
6
89.8, 160.1, 152.5, 151.0, 149.7, 142.8, 136.8, 132.7, 128.3, 122.7, 116.3, 106.3, 105.1, 55.7,
-1
5.6; IR (neat, cm ): 3140, 3035, 2846, 1683, 1570, 1496, 1365, 1145, 1001, 798, 675; MS(EI)
+
+
m/z (%): 366[M] ; HRMS(EI): [M] Calcd for C H ClN O S : 366.99779, Found: 365.98880.
1
5
11
2
3 2
4
.3.10. (Z)-5-((6-Chloro-[1,3]dioxolo[4,5-g]quinolin-7-yl)methylene)-2-thioxothiazolidin-4-one
19)
Red solid; Yield: 76%; mp: 385-388 C. H NMR (300 MHz, DMSO-d
(
0
1
6
): δ 8.07 (s, 1H), 7.55 (s,
1
3
1
1
3
H), 7.29 (s, 1H), 6.81 (s, 1H), 6.14 (s, 2H); C NMR (500 MHz, DMSO-d ): δ 197.6, 169.4,
6
-1
60.2, 152.1, 143.9, 143.2, 137.3, 127.9, 125.1, 121.1, 113.8, 105.6, 102.3, 94.8; IR (neat, cm ):
153, 3078, 2848, 2358, 2341, 1683, 1645, 1558, 1436, 1209, 1166, 026, 933, 817, 680;
+
MS(ESI) m/z (%): 349[M-H] . Anal. calcd for C H ClN O S : C, 47.93; H, 2.01; N, 7.99; S,
14
7
2
3 2
1
8.28. Found: C, 47.60; H, 1.82; N, 7.40; S, 17.98.
4
.3.11. (Z)-5-((2-Chlorobenzo[h]quinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (20)
0
1
Yellow solid; Yield: 80%; mp: 299-301 C. H NMR (300 MHz, DMSO-d ): δ 8.98 (d, 1H, J
6
=
7.71 Hz), 8.49 (s, 1H), 8.08 (m, 2H), 8.03 (d, 1H J = 7.71 Hz), 7.82 (m, 2H), 7.81 (s, 1H); IR
-
1
+
(
[
KBr, cm ): 3414, 3152, 1697, 1618, 1574, 1213, 899; MS(EI) m/z (%): 356 [M] ; HRMS(EI):
+
M] Calcd for C H ClN OS : 355.98448. Found: 355.98440.
1
7
9
2
2
4
2
2
.4.
General procedure for the synthesis of rhodanine derivatives (21-31)
-Chloroquinoline-3-carbaldehyde 3a-n (0.0045 mol) was taken in round bottom flask added to
-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid 8b (0.0045 mol) and to this sodium acetate (0.0135
mol) was added. Acetic acid (20 ml) was added as solvents The mixture was reflux for 4 h at
0
1
10 C and cooled at rt and poured into water, compound (21-31) was formed. It was then
filtered through the suction pump, washed with water to remove excess of acetic acid and
recrystallized from methanol.
4
.4.1. (Z)-5-((2-Chloroquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one. (21)
10

ACCEPTED MANUSCRIPT
0
1
Yellow solid; Yield: 66%; mp: 348-351 C. H NMR (300 MHz, DMSO-d
6
): δ 12.28 (bs, 1H),
8
8
1
.43 (s, 1H), 7.81 (d, 1H, J = 8.12 Hz), 7.78 (s, 1H), 7.62 (t, 1H, J = 7.55 Hz), 7.36 (d, 1H, J =
1
3
.12 Hz), 7.26 (t, 1H, J = 7.55 Hz), 4.73 (s, 2H); C NMR (500 MHz, DMSO-d ): δ 196.2,
6
67.3, 166.8, 161.3, 145.6, 139.4, 132.7, 130.2, 129.3, 124.3, 123.5, 122.8, 119.3, 115.3, 44.9;
-1
IR(KBr, cm ): 2983, 2841, 2362, 2331, 1697, 1627, 1319, 1199, 1058, 746, 734. MS(ESI) m/z
+
(
%): 355[M-H] . Anal. calcd for C15
H
9
ClN
2
O
3
S
2
: C, 49.38; H, 2.49; N, 7.68; S, 17.58. Found: C,
4
9.71; H, 2.46; N, 7.33; S, 17.19.
4
.4.2. (Z)-2-(5-((2-Chloro-8-methylquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-
yl)acetic acid (22)
Yellow solid; Yield: 69%; mp: 359-361 C. H NMR (300 MHz, DMSO-d
0
1
6
): δ 11.39 (bs, 1H),
8
8
1
.18 (s, 1H), 7.81 (s, 1H), 7.54 (d, 1H, J = 8.49 Hz), 7.37 (d, 1H, J = 8.49 Hz), 7.10 (t, 1H, J =
1
3
.49 Hz), 4.72 (s, 2H) 2.47 (s, 3H); C NMR (500 MHz, DMSO-d ): δ 196.8, 167.9, 167.3,
6
61.5, 146.9, 138.4, 134.5, 130.7, 128.0, 124.7, 124.4, 124.0, 123.1, 119.9, 45.4, 17.6; IR (neat,
-1
cm ): 3184, 3012, 2970, 2358, 1716, 1701, 1624, 1313, 1197, 1052, 746. MS(ESI) m/z (%):
+
3
5
77[M-H] . Anal. calcd for C16
H11ClN
2
O
3
2
S : C, 50.72; H, 2.93; N, 7.39; S, 16.93. Found: C,
1.08; H, 3.29; N, 7.56; S, 17.20.
4
.4.3. (Z)-2-(5-((2-Chloro-8-ethylquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic
acid (23)
Yellow solid; Yield: 70%; mp: 352-356 C. H NMR (300 MHz, DMSO-d
0
1
6
): δ 11.79 (bs, 1H),
8
.72 (s, 1H), 8.07 (s, 1H), 7.96 (d, 1H, J = 7.36 Hz), 7.79 (d, 1H, J = 7.36 Hz), 7.52 (t, 1H, J
1
3
=
7.36 Hz), 5.04 (s, 2H), 3.20 (qt, 2H, J = 7.36 Hz), 1.48 (t, 3H, J = 7.36 Hz); C NMR (500
MHz, DMSO-d
6
): δ 196.8, 167.9, 167.3, 161.6, 147.0, 137.6, 132.9, 130.7, 130.3, 128.1, 124.3,
-
1
1
1
3
24.0, 123.3, 120.1, 45.4, 23.1, 14.7; IR(KBr, cm ): 3268, 2979, 2360, 1706, 1613, 1327, 1193,
+
+
2 3 2
055, 742. MS(ESI) m/z (%): 391[M-H] ; HRMS(EI):[M] Calcd for C17H13ClN O S :
92.00561, Found: 392.00462 .
4
.4.4. (Z)-2-(5-((2-Chloro-6-methylquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-
yl)acetic acid (24)
11

ACCEPTED MANUSCRIPT
0
1
Yellow solid; Yield: 69%; mp: 356-358 C. H NMR (300 MHz, DMSO-d
6
): δ 12.21 (bs, 1H),
8
.33 (s, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 7.45 (d, 1H, J = 8.49 Hz), 7.25 (d, 1H, J = 8.49 Hz), 4.72
1
3
(
s, 2H), 2.35 (s, 3H); C NMR (500 MHz, DMSO-d ): δ 196.8, 167.9, 167.3, 160.9, 146.0,
6
-
1
1
2
38.0, 134.7, 132.5, 131.1, 130.9, 129.1, 124.6, 119.8, 115.7, 45.4, 20.8; IR(KBr, cm ): 3134,
+
984, 2742, 2358, 1694, 1340, 1211, 1062, 748; MS(ESI) m/z (%): 379 [M+H] ; Anal. calcd for
16 2 3 2
C H11ClN O S : C, 50.72; H, 2.93; N, 7.39; S, 16.93. Found: C, 51.09; H, 3.28; N, 7.72; S,
1
6.98.
4
.4.5. (Z)-2-(5-((2-Chloro-6,8-dimethylquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-
yl)acetic acid (25)
Yellow solid; Yield: 70%; mp: 346-348 C. H NMR (300 MHz, DMSO-d
.42 (s, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 4.82 (s, 2H), 2.51 (s, 3H), 2.43 (s, 3H); C
NMR (500 MHz, DMSO-d ): δ 196.1, 166.9, 161.0, 146.2, 136.0, 135.7, 135.1 131.9, 130.5,
0
1
6
): δ 11.49 (bs, 1H),
1
3
8
6
-
1
1
1
26.9, 123.9, 123.4, 119.5, 115.3, 45.2, 20.2, 17.0; IR (KBr, cm ): 3421, 3179, 2924, 1701,
+
+
632, 1336, 1205, 1061; MS(ESI) m/z (%): 391[M-H] ; HRMS(ESI): [M-H] Calcd for
Cl: 390.9977, Found: 390.9961.
17 13 2 3 2
C H N O S
4
.4.6. (Z)-2-(5-((2-Chloro-5,8-dimethylquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-
yl)acetic acid (26)
Yellow solid; Yield: 70%; mp: 341-343 C. H NMR (300 MHz, DMSO-d ): δ 11.25 (bs, 1H),
0
1
6
8
.47 (s, 1H), 7.78 (s, 1H), 7.30 (d, 1H, J = 7.36 Hz), 6.97 (d, 1H, J = 7.36 Hz), 4.67 (s, 2H), 2.50
1
3
(
s, 3H), 2.35 (s, 3H); C NMR (500 MHz, DMSO-d ): δ 196.1, 166.5, 160.2, 143.3, 137.9,
6
-
1
1
3
34.5, 133.5, 130.6, 123.4, 122.8, 122.7, 121.3, 118.2, 117.9, 44.7, 17.8, 16.5; IR (KBr, cm ):
+
422, 2926, 1711, 1624, 1334, 1239, 1205, 1059; MS(ESI) m/z (%): 391[M-H] ; HRMS(ESI):
+
[
M+H] Calcd for C H N O S Cl: 392.9977, Found: 392.9978.
1
7
13
2
3 2
4
.4.7. (Z)-2-(5-((2-Chloro-6-methoxyquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-
yl)acetic acid (27)
Red solid; Yield: 74%; mp: 319-321 C. H NMR (300 MHz, DMSO-d ): δ 12.11 (bs, 1H), 8.07
0
1
6
(s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.29 (d, 1H, J = 9.25 Hz), 7.12 (d, 1H, J = 9.25 Hz), 4.73 (s,
12

ACCEPTED MANUSCRIPT
1
3
2
1
2
6
H), 3.84 (s, 3H); C NMR (500 MHz, DMSO-d ): δ 195.9, 166.7, 160.0, 154.6, 144.5, 134.1,
-1
30, 129.8, 124.5, 123.5, 122.6, 119.8, 116.6, 109.6, 55.4, 45.0; IR (KBr, cm ): 3145, 3025,
-
915, 2360, 1714, 1667, 1336, 1198, 1057, 743; MS(ESI) m/z (%): 433[M+K] . Anal. calcd for
16 2 4 2
C H11ClN O S : C, 48.67; H, 2.81; N, 7.09; S, 16.24. Found: C, 49.01; H, 2.86; N, 7.33; S,
1
6.54.
4
.4.8. (Z)-2-(5-((2-Chloro-5,8-dimethoxyquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin -3-
yl) acetic acid (28)
Red solid; Yield: 75%; mp: 339-342 C. H NMR (300 MHz, DMSO-d
0
1
6
): δ 11.52 (bs, 1H), 8.45
(s, 1H), 7.82 (s, 1H), 7.20 (d, 1H, J = 8.87 Hz), 6.71 (d, 1H, J = 8.87 Hz), 4.72 (s, 2H), 3.90 (s,
1
3
3
1
6
H), 3.85 (s, 3H); C NMR (500 MHz, DMSO-d ): δ 195.3, 166.5, 159.8, 150.1, 139.6, 138.9,
36.6, 128.8, 123.5, 123.2, 115.8, 114.9, 110.5, 102.7, 56.9, 56.6, 44.7. MS(ESI) m/z (%): 448
+
[
M+Na] ; Anal. calcd for C H ClN O S : C, 48.06; H, 3.08; N, 6.59; S, 15.09. Found: C,
1
7
13
2
5 2
4
8.39; H, 3.45; N, 6.57; S, 15.42.
4
.4.9. (Z)-2-(5-((2-Chloro-6,7-dimethoxyquinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin -3-
yl)acetic acid (29)
Red solid; Yield: 75%; mp: 334-336 C. H NMR (300 MHz, DMSO-d ): δ 12.09 (bs, 1H), 8.20
0
1
6
1
3
(
s, 1H), 7.74 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 4.69 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H); C NMR
(
500 MHz, DMSO-d ): δ 195.9, 166.7, 160.0, 154.6, 144.5(2), 134.1, 129.8, 124.5, 123.5, 122.6,
6
-1
1
19.8, 116.6, 109.6, 97.4, 55.4, 45.0; IR (neat, cm ): 2915, 2358, 2330, 1716, 1697, 1508, 1217,
+
1
196, 1001, 846, 738; MS(ESI) m/z (%): 425[M+H] . Anal. calcd for C H ClN O S : C, 48.06;
1
7
13
2
5 2
H, 3.08; N, 6.59; S, 15.09. Found; C, 48.12; H, 2.81; N, 6.98; S, 15.39.
4
.4.10. (Z)-2-(5-((6-Chloro-[1,3]dioxolo[4,5-g]quinolin-7-yl)methylene)-4-oxo-2-
thioxothiazolidin-3-yl)acetic acid (30)
0
1
Red solid; Yield: 75%; mp: 371-374 C. H NMR (300 MHz, DMSO-d ): δ 11.00 (bs, 1H), 8.27
6
1
3
(
s, 1H), 7.91 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.10 (s, 2H), 4.69 (s, 2H); C NMR (500 MHz,
DMSO-d ): δ 197.6, 169.5, 160.2, 152.1, 143.9, 143.2, 137.3, 127.9, 125.2, 121.2, 113.9, 105.6,
02.5, 102.2, 94.9, 44.8; IR (neat, cm ): 3003, 2941, 2358, 2341, 1635, 1541, 1456, 1232, 1029,
6
-1
1
13

ACCEPTED MANUSCRIPT
+
8
29. MS(ESI) m/z (%): 407[M-H] ; Anal. calcd for C16
H
9
ClN
2
O
5
S
2
: C, 47.00; H, 2.22; N, 6.85;
S, 15.69. Found: C, 47.37; H, 2.50; N, 6.77; S, 16.01.
4
.4.11.
yl)acetic acid (31)
Yellow solid; Yield: 85%; mp: 279-281 C. H NMR (300 MHz, DMSO-d
(Z)-2-(5-((2-Chlorobenzo[h]quinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-
0
1
6
): δ 12.09 (bs, 1H),
-
1
8
1
.35 (s, 1H), 7.86 (m, 4H), 7.78 (s, 1H), 7.59 (m, 2H), 4.50 (s, 2H); IR (KBr, cm ): 3229, 1753,
–
–
701, 1575, 1324, 1188, 1055, 901; MS(ESI) m/z (%): 413[M-H] ; HRMS(ESI): [M-H] Calcd
Cl: 412.9821. Found: 412.9806.
11 2 3 2
for C19H N O S
4
2
3
.5.
General procedure for the synthesis of rhodanine derivatives (32-34)
-Chloroquinoline-3-carbaldehyde 3f-g (0.0045 mol) was taken in round bottom flask added to
-phenyl-2-thioxothiazolidin-4-one 8c (0.0045 mol) and to this sodium acetate (0.0135 mol) was
0
added. Acetic acid (20 ml) was added as solvents. The mixture was reflux for 4 h at 110 C and
cooled at rt and poured into water compound (32-34) was formed. It was then filtered through
the suction pump, washed with water to remove excess of acetic acid and recrystallized from
methanol.
4
.5.1. (Z)-5-((2-Chlorobenzo[h]quinolin-3-yl)methylene)-3-phenyl-2-thioxothiazolidin-4-one
32)
Yellow solid; Yield: 80%; mp: 288-290 C. H NMR (300 MHz, DMSO-d
(
0
1
6
): δ 8.65 (s, 1H), 8.20
(
(
d, 1H, J = 8.82 Hz), 8.02 (s, 1H), 7.85 (m, 4H), 7.57 (m, 5H), 7.47 (d, 1H, J = 8.82 Hz); IR
-1
+
KBr, cm ): 3032, 1724, 1639, 1570, 1235, 1143, 902; MS(EI) m/z (%): 432 [M] ; Anal. Calcd
OS : C, 63.81; H, 3.03; N, 6.47; S, 14.81. Found: C, 64.16; H, 2.92; N, 6.35; S,
for C23
H13ClN
2
2
1
4.80.
4
.5.2. (Z)-5-((2-Chloro-6,8-dimethylquinolin-3-yl)methylene)-3-phenyl-2-thioxothiazolidin-4-one
(
33)
Yellow solid; Yield: 74%; mp: 357-359 C. H NMR (300 MHz, DMSO-d
0
1
6
): δ 8.29 (s, 1H), 7.74
-1
(
s, 1H), 7.54 (m, 5H), 7.44 (s, 1H), 7.30 (s, 1H), 2.41 (s, 3H), 2.31 (s, 3H); IR (KBr, cm ):
+
3
422, 3032, 1721, 1655, 1347, 1243, 1126; MS(EI) m/z (%): 392[M] . Anal. calcd for
14

ACCEPTED MANUSCRIPT
C
21
H
15ClN
2
OS
2
: C, 61.38; H, 3.68; N, 6.82; S, 15.61. Found: C, 61.72; H, 3.36; N, 6.60; S,
1
5.80.
4
.5.3. (Z)-5-((2-Chloro-5,8-dimethylquinolin-3-yl)methylene)-3-phenyl-2-thioxothiazolidin-4-
one (34)
Yellow solid; Yield: 74%; mp: 366-368 C. H NMR (300 MHz, DMSO-d
0
1
6
): δ 8.52 (s, 1H), 7.81
(s, 1H), 7.52 (m, 5H), 7.36 (d, 1H J = 7.63 Hz ), 7.32 (d, 1H J = 7.63 Hz), 2.52 (s, 3H), 2.38 (s,
1
3
3
1
3
H): C NMR (500MHz, DMSO-d ): δ 197.1, 167.4, 160.7, 143.2, 138.2, 135.4, 134.8, 133.7,
6
-1
30.0(2), 129.2(2), 128.6, 125.9, 124.6, 123.7, 123.4, 121.7, 118.3, 18.2, 16.9; IR (KBr, cm ):
+
430, 3162, 3032, 1726, 1654, 1347, 1243, 1126, 746; MS(EI) m/z (%): 392[M] ; Anal. calcd for
21 2 2
C H15ClN OS : C, 61.38; H, 3.68; N, 6.82; S, 15.61. Found: C, 61.68; H, 4.00; N, 6.48; S,
1
5.96.
4
.6.
General procedure for the synthesis of rhodanine derivatives (35-39)
Subtuted-2-(piperidin-1-yl)quinoline-3-carbaldehyde 5a-e (0.0045 mol) was taken and added to
8
a-b (0.0045 mol) and to this sodium acetate (0.0135 mol) was added. Acetic acid (20 ml) was
0
added as solvents. The mixture was refluxed for 4 h at 110 C and cooled at rt and poured into
water compound (35-39). was formed. It was then filtered through the suction pump, washed
with water to remove excess of acetic acid and recrystallzied from methanol.
4
.6.1. (Z)-5-((8-Methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)-2-thioxothiazolidin-4-one
35)
Red solid; Yield: 71%; mp: 288-290 C. H NMR (300 MHz, DMSO-d ): δ 8.05 (s, 1H), 7.66 (s,
(
0
1
6
1
2
H), 7.55 (d, 1H, J = 7.36 Hz), 7.46 (d, 1H, J = 7.36 Hz), 7.23 (t, 1H, J = 7.36 Hz), 3.34 (s, 4H),
1
3
.66 (s, 3H), 1.74 (m, 6H); C NMR (500 MHz, DMSO-d ): δ 196.0, 167.0, 158.1, 144.5(2),
6
-
1
38.7, 137.5, 133.6, 127.4(2), 126.3, 124.2, 122.4(2), 119.3, 51.1, 25.1, 24.0, 17.0; IR (KBr, cm
1
+
)
: 3165, 3028, 2850, 2363, 1712, 1435, 1218, 1068, 741; MS(EI) m/z (%): 369 [M] ;
+
HRMS(EI): [M] Calcd for C H N OS : 369.09695. Found: 369.09590.
1
9
19
3
2
4
.6.2. (Z)-5-((6-Methyl-2-morpholinoquinolin-3-yl)methylene)-2-thioxothiazolidin-4-one (36)
15

ACCEPTED MANUSCRIPT
0
1
Yellow solid; Yield: 70%; mp: 288-290 C. H NMR (300 MHz, DMSO-d
6
): δ 8.31 (s, 1H), 7.78
(s, 1H), 7.70 (d, 1H, J = 8.49 Hz), 7.60 (d, 1H, J = 8.49 Hz), 7.43 (s, 1H), 3.78 (m, 4H), 3.25 (m,
1
3
4
1
2
H), 2.46 (s, 3H); C NMR (500 MHz, DMSO-d ): δ 195.9, 169.3, 158.1, 145.0, 137.7, 134.3,
6
-1
33.3, 127.6, 127.3, 127.2, 126.8, 124.2, 120.4, 65.8(2), 50.7(2), 20.8; IR(KBr, cm ): 3061,
+
+
864, 2363, 1712, 1470, 1224, 1106, 822; MS(EI) m/z (%): 372[M+H] . HRMS(EI): [M] Calcd
: 371.07622. Found: 371.07522.
17 3 2 2
for C18H N O S
4
.6.3. (Z)-2-(4-Oxo-5-((2-(piperidin-1-yl)quinolin-3-yl)methylene)-2-thioxothiazolidin-3-
yl)acetic acid (37)
Yellow solid; Yield: 70%; mp: 337-340 C. H NMR (300 MHz, DMSO-d ): δ 12.24 (bs, 1H),
0
1
6
8
7
3
.34 (s, 1H), 7.90 (d, 1H, J = 7.16 Hz), 7.85 (s, 1H), 7.74 (d, 1H, J = 7.16 Hz), 7.67 (t, 1H, J =
-1
.16 Hz), 7.40 (t, 1H, J = 7.16 Hz), 4.75 (s, 2H), 3.40 (s, 4H), 1.71 (m, 6H); IR (KBr, cm ):
+
+
150, 2939, 2362, 1650, 1337, 1213, 1060, 750; MS(EI) m/z (%): 413[M] ; HRMS(EI): [M]
: 413.08678. Found: 413.08660.
19 3 3 2
Calcd for C20H N O S
4
.6.4. (Z)-2-(5-((8-Ethyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)-4-oxo-2-tioxothiazolidin-3-
yl)acetic acid (38)
Red solid; Yield: 74%; mp: 280-284 C. H NMR (300 MHz, DMSO-d ): δ 11.00 (bs, 1H), 8.17
0
1
6
(s, 1H), 7.86 (s, 1H), 7.60 (d, 1H, J = 7.90 Hz), 7.48 (d, 1H, J = 6.61 Hz), 7.28 (t, 1H, J = 7.90
Hz) 4.76 (s, 2H), 3.36 (s, 4H), 3.15 (q, 2H, J = 7.55 Hz), 1.74 (m, 6H), 1.34 (t, 3H, J = 7.55 Hz).
-1
+
IR (KBr, cm ): 2972, 2358, 1715, 1625, 1336, 1200, 1058, 751. MS(ESI) m/z (%): 440[M-H] .
Anal. calcd for C H N O S : C, 59.84; H, 5.25; N, 9.52; S, 14.52. Found: C, 59.48; H, 4.96; N,
2
2
23
3
3 2
9
.14; S, 14.14.
4
3
.6.5. (Z)-2-(5-((6-Methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)-4-oxo-2-thioxothiazolidin-
-yl)acetic acid (39)
0
1
Red solid; Yield: 72%; mp: 286-289 C. H NMR (300 MHz, DMSO-d ): δ 11.00 (bs, 1H), 8.34
6
(s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.69 (d, 1H, J = 8.40 Hz), 7.58 (d, 1H, J = 8.40 Hz), 4.73 (s,
1
3
2
1
4
H), 3.27 (s, 4H), 2.49 (s, 3H), 1.69 (m, 6H); C NMR (500 MHz, DMSO-d
6
): δ 193.5, 167.1,
66.4, 158.7, 145.4, 138.4, 133.9, 133.4, 130.4, 130.1, 127.3, 126.7, 123.9, 122.8, 120.3, 51.3,
-1
5.4, 30.6, 25.2, 23.9, 20.7; IR (KBr, cm ): 2919, 2848, 2357, 1712, 1583, 1383,1201, 825;
16

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+
+
MS(ESI) m/z (%): 426 [M-H] ; HRMS(EI): [M] Calcd for C21
H
21
N
3
O
3
S
2
: 427.10243. Found:
4
27.10220.
4
.7. Biological activity
4
.7.1 Cell culture
MDAMB231 and MCF7 cell lines (Breast cancer) were gifted sample by Dr Radha, CCMB, Hyderabad,
India; HGC and MKN74 cell lines (Gastric cancer) and DU-145, PC 3 cell lines (Prostate cancer) were
obtained from Cell Bank, RIKEN Bio Resource Centre, Japan. DMEM, MTT [3-(4, 5- dimethylthiazol-2-
yl)-2, 5-diphenyl tetrazolium bromide], Trypsin, EDTA were purchased from Sigma Chemicals Co
(
St.Louis, MO), Fetal bovine serum (FBS) was purchased from Gibson, USA and 96 well flat bottom
tissue culture plates were purchased from Tarson. HGC, MKN74 cell lines were grown as adherent in
MEM, MDAMB231 and MCF 7 cell lines in DMEM and DU-145, PC 3 cell lines in RPMI media
respectively supplemented with 10% fetal bovine serum, 100 µg / ml penicillin, 200 µg/ml streptomycin,
2
mM L-glutamine, and culture was maintained in a humidified atmosphere with 5% CO2.
4
.7.2 Cytotoxicity evaluation
Cytotoxicity of the compounds was determined by MTT assay based on mitochondrial reduction
4
of yellow MTT tetrazolium dye to a highly colored blue formazan product. 1x10 Cells (counted
by Trypan blue exclusion dye method)) in 96- well plates were incubated with formulations with
0
series of concentrations for 48 hrs at 37 C in DMEM with 10% FBS medium. Then the above
media was replaced with 90µl of fresh serum free media and 10 µl of MTT reagent (5mg/ml) and
0
plates were incubated at 37 C for 4h, there after the above media was replaced with 200µl of
DMSO and the absorbance was measured at 570nm on a spectrophotometer (spectra max,
Molecular devices) and IC values were determined.
50
Acknowledgements
The authors thank the Director, CSIR-Indian Institute of Chemical Technology (CSIR-IICT) for
encouragement. VJR thanks CSC-0108-ORIGIN project. VR and BAR thanks thanks CSIR,
New Delhi, for fellowships. KS and VGMN thank NIPER-Hyderabad, Department of
Pharmacetuicals, Govt of India for support.
17

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Captions for Figures and Schemes
1
2
3
4
5
6
7
8
.
.
.
.
.
.
.
.
Scheme 1. Synthesis of 2-chloroquinoline-3-carboxaldehyde. Reagents and conditions: (a) Et
HCl , 0 C, 1h; (b) POCl , DMF, 16h, reflux.
3
N,
º
3
3
Scheme 2. Synthesis of 2-(piperidin-1-yl)quinoline-3-carboxaldehyde: Reagents and conditions:
a) K CO (2eq.), reflux, 15h.
(
2
3,
Scheme 3. Synthesis of rhodanine, rhodanine aceticacid and phenylrhodanine. Reagents and
conditions: (a) CS , NH ; (b) ClCH COONa, 85-90 C, HCl
2
3
2
º
Scheme 4. Synthesis of rhodanine derivatives: Reagents and conditions: (a) NaOAc/AcOH,
reflux, 4 h.
Scheme 5. Synthesis of rhodanine derivatives: Reagents and conditions: (a) NaOAc/AcOH,
reflux, 4 h.
Scheme 6. Synthesis of rhodanine derivatives: Reagents and conditions: (a) NaOAc/AcOH,
reflux, 4 h.
Scheme 7. Synthesis of rhodanine derivatives: Reagents and conditions: (a) NaOAc/AcOH,
reflux, 4 h.
Figure1: Dose response curve of rhodanine derivatives on human cancer cell lines
determined by MTT assay after 48h treatment.
22

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Table 1. Synthesis of rhodanine analogues (9-39)
Sl.No.
Sub.Quinoline
CHO
Cl
Sub.Rhodanine
Product
Yield(%)
66
O
01
3a
NH
S
S
S
N
N
N
N
Cl
6
a
S
O
0
9
CHO
Cl
NH
0
2
3
3a
69
N
Cl
Me
Et
S
6
b
Me
Et
1
0
O
CHO
Cl
3a
NH
72
69
69
0
N
Cl
S
6
c
11
O
CHO
0
4
5
NH
3
a
a
S
S
S
Me
Me
N
Cl
Me
Me
N
Cl
Cl
Cl
S
S
O
6d
12
CHO
Cl
3
0
NH
N
N
6e
S
O
13
Me
CHO
Cl
Me
3a
NH
S
72
06
N
N
Me
14
Me
Me
6f
Me
O
CHO
Cl
0
7
8
3a
3a
NH
72
N
N
Cl
S
Me 6g
Me
15
O
MeO
CHO
Cl
MeO
0
NH
75
76
S
N
N
16
Cl
6h
S
OMe
OMe
OMe
O
CHO
Cl
09
NH
3a
S
N
N
Cl
17
S
OMe 6i

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Table 2: Inhibitory effects of selected compounds on the growth of human cancer cell lines
Gastric cancer (HGC and MNK 74), Breast cancer (MCF-7 and MDA-MB 231), Prostate cancer
(DU145 and PC3)
Comp-
ound
No.
Gastric Cancer
HGC MNK 74
NA >100
Breast Cancer
MDA MB
Prostate cancer
MCF 7
DU145
PC 3
231
>100
9
6.3±0.8
>100
>100
64.2±18.7
51.3±4.6
35.3±2.2
74.5±7.4
19.1±1.2
15.3±3.7
19.8±5.6
14.3±5.2
24.05±1
12.6±4.1
>100
>100
>100
1
1
1
1
1
1
1
1
1
2
2
2
2
3
3
3
3
0
1
2
3
4
5
6
8
9
0
3
5
6
1
5
6
9
33.9±3.3
63.0±1.5
69.1±9.8
76.7±5.6
9.7±1.5
7.2±0.5
7.3±0.3
14.4±5.4
>100
>100
>100
>100
>100
>100
>100
>100
10.5±1.3
35.7±14.6
>100
>100
>100
>100
>100
>100
37.2±7.8
96.9±11.7
>100
>100
>100
9.5±0
>100
55.6±27.9
>100
39.1±0.2
>100
>100
>100
>100
>100
>100
>100
>100
>100
28.9±4.2
71.7±1.6
40.9±4.3
42.5±0.6
40.1±2.8
18.9±2
>100
11.8±2.2
>100
74.4±4.7
>100
>100
>100
>100
>100
>100
>100
19.1±1.1
40.2±4.7
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
35.9±1.2
>100
>100
>100
16.6±2.5
36.9±10.6
20.6±1
25.7±7.03
>100
105.6±4.4
11.2±0
>100
41.2±15.8
>100
13.9±2.3
>100
13.2±6.5
Rosigli
ND
ND
ND
ND
16.0±5.0
20.3±6.2
a
tazone
a
ND: Not Determined;

ACCEPTED MANUSCRIPT
Scheme 1.
Scheme 2.
Scheme 3.